Shared cerebral metabolic pathology in non-transgenic animal models of Alzheimer's and Parkinson's disease

Abstract

Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common chronic neurodegenerative disorders, characterized by motoric dysfunction or cognitive decline in the early stage, respectively, but often by both symptoms in the advanced stage. Among underlying molecular pathologies that PD and AD patients have in common, more attention is recently paid to the central metabolic dysfunction presented as insulin resistant brain state (IRBS) and altered cerebral glucose metabolism, both also explored in animal models of these diseases. This review aims to compare IRBS and alterations in cerebral glucose metabolism in representative non-transgenic animal PD and AD models. The comparison is based on the selectivity of the neurotoxins which cause experimental PD and AD, towards the cellular membrane and intracellular molecular targets as well as towards the selective neurons/non-neuronal cells, and the particular brain regions. Mitochondrial damage and coexpression of insulin receptors, glucose transporter-2 and dopamine transporter on the membrane of particular neurons as well as astrocytes seem to be the key points which are further discussed in a context of alterations in insulin signalling in the brain and its interaction with dopaminergic transmission, particularly regarding the time frame of the experimental AD/ PD pathology appearance and the correlation with cognitive and motor symptoms. Such a perspective provides evidence on IRBS being a common underlying metabolic pathology and a contributor to neurodegenerative processes in representative non-transgenic animal PD and AD models, instead of being a direct cause of a particular neurodegenerative disorder.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The absence of gastrointestinal redox dyshomeostasis in the brain-first rat model of Parkinson’s disease induced by bilateral intrastriatal 6-hydroxydopamine

“…Considering that other neurotoxin-based „brain-first“models of neurodegeneration (e.g. the streptozotocin-induced rat model of sporadic Alzheimer’s disease [29] with some resemblance to the 6-OHDA models of PD [30]) demonstrate pronounced redox dyshomeostasis that may contribute to the progression of the disease phenotype [31, 32], we hypothesized that intrastriatal administration of 6-OHDA may produce similar alterations and promote systemic and neuro-inflammation in the rat model of PD contributing to the progression of neuropathology.…”

Disbalance of the Duodenal Epithelial Cell Turnover and Apoptosis Accompanies Insensitivity of Intestinal Redox Homeostasis to Inhibition of the Brain Glucose-Dependent Insulinotropic Polypeptide Receptors in a Rat Model of Sporadic Alzheimer’s Disease

“…Streptozotocin is a nitrosourea compound used for modeling insulin resistance and diabetes mellitus type 1 in rodents following parenteral administration [42, 43]. After intracerebroventricular administration, STZ has been shown to cause cerebral pathophysiological changes resembling those found in sAD, such as the IRBS [44, 45], glucose hypometabolism [45, 46], oxidative stress [47], mitochondrial dysfunction [44], neuroinflammation [48, 49], cholinergic deficits [50], accumulation of amyloid β [51] and hyperphosphorylated tau [52], and the development of cognitive deficits [53].…”

Association of Cognitive Deficit with Glutamate and Insulin Signaling in a Rat Model of Parkinson's Disease

“…Interestingly, in striatum, TH was found positively correlated with ERK and pI3K, suggesting the importance of MAPK/ERK and PI3K/AKT signaling pathways in catecholamine synapses not necessarily connected with IR pathway (Figure 7). Summarizing the results, we can assume that disturbed dopamine signaling may be, to a lesser extent, transduced to insulin signaling and its downstream targets, as a secondary, collateral damage [50] like the one seen in HPT, but it probably depends on the 6-OHDA dose and the location of administration. In addition, intranasal insulin improves mitochondrial function, alleviates motor deficits and protects against substantia nigra dopaminergic neuronal loss in 6-OHDA rat model [64,65], suggesting neuroprotective insulin action.…”

“…Striatal 6-OHDA injections better reproduce the early stages of PD, so this approach is well suited to the study of non-motor symptoms, since these ailments often appear during the prodromal phase of PD [49], and once again indicating the importance of striatum in spatial learning and memory. 6-OHDA administration leads to damaging noradrenergic neurons as well, which can be associated with both central (cognitive impairment, depression, anxiety, olfactory deficit) as well as peripheral (cardiovascular, gastrointestinal) non-motor symptoms [50]. Interestingly, only in HPT, parameter measuring fear-conditioned memory, in addition to MWM, is one of the important one that explains the difference between CTR and OHDA groups.…”